γ-Aminobutyric acid (GABA) is a typical inhibitory neurotransmitter which activates both an ionotropic GABAA and a metabotropic GABAB receptor. The GABAB receptor is expressed in most of both presynaptic terminals and postsynaptic portions in the mammalian brain and adjusts the inhibitory synaptic transmission, and it thus has a wide range of physiological and psychopathological actions. The GABAB receptor is a G protein coupled receptor (GPCR), has a seven-transmembrane domain, and is structurally classified to a Class C. This Class C GPCRs have a particularly large extracellular region and functions by forming a homo- or hetero-dimer(s) (Neuropharmacology, 2011, January, vol. 60 (1), p. 82-92). The GABAB receptor forms a hetero-dimer of GABAB1 and GABAB2, and exerts a function as a receptor by the cooperation between the subunits. That is, only the GABAB1 has a function for allowing a ligand of an orthosteric GABAB receptor to bind, and promotes the coupling and activating function of a G protein of GABAB2. The activated GABAB receptor inhibits an adenylate cyclase and controls the openings of K+ channels (GIRK) conjugated with G protein and voltage-dependent calcium channels.
From the recent studies, there have been reports that mental disorders such as a cognitive impairment and the like are caused by dysfunction of GABA-mediated nerves in a patient (Trends in Neurosciences, 2012, vol. 35 (1), p. 57-67; Molecular Psychiatry, 2003, vol. 8 (8), p. 721-737, 715; Frontiers in Psychiatry, 2012, vol. 3, p. 51; and Neuroscience & Biobehavioral Reviews, 2012, October, vol. 36 (9), p. 2044-2055).
Baclofen is a GABAB receptor-selective agonist and is clinically used. In preclinical trials, it has been reported that baclofen improves methanephetamine-induced cognitive impairment in mice (European Journal of Pharmacology, 2009, vol. 602 (1), p. 101-104); methanephetamine- and MK-801-induced prepulse inhibition disorder (Neuropsychopharmacology, 2008, December, vol. 33 (13), p. 3164-3175); and social behavioral disorder, spatial memory disorder, and γ-band brain waves in genetically modified mice with NMDA receptor hypofunction (Translational Psychiatry, 2012, Jul. 17, vol. 2, p. e142).
It has been reported that R-baclofen is effective in a fragile X syndrome patient and an autism spectrum disorder (Science Translational Medicine, 2012, Sep. 19, vol. 4 (152), p. 152ra127; and Journal of Autism and Development Disorders., 2014, April, vol. 44 (4), p. 958-964). It has also been reported that FMR1, a gene causing a fragile X syndrome, has a significant effect on the expression of numerous genes associated in an autism spectrum disorder (Nature, 2012, December, vol. 492, p. 382-386; and Cell, 2011, July, vol. 146 (2), p. 247-261).
Baclofen has been clinically used for the treatment of spasticity, contracture, or rigidity, which is caused from spinocerebellar degeneration, spinal cord injury, multiple sclerosis, amyotrophic lateral sclerosis, cerebral palsy, stroke, head trauma, or the like (Neurology, 2004, Oct. 26, vol. 63 (8), p. 1357-1363). It has also been reported that baclofen is effective in anxiety disorder (Journal of Pharmacology and Experimental Therapeutics, 2004, vol. 310, P. 952-963); substance addiction, for example, addiction to drugs such as nicotine, cocaine, morphine, and the like, or alcoholism (Advances in Pharmacology, 2010, vol. 58, p. 373-396; Drug and Alcohol Dependence, 2002, Feb. 1, vol. 65 (3), p. 209-220; and Synapse, 2003, October, vol. 50 (1), p. 1-6); pain, for example, neuropathic pain (European Journal of Pain, 2004, August, vol. 8(4), p. 377-383); and reflux esophagitis (Neurogastroenterology and Motility, 2012, June, vol. 24 (6), p. 553-559, e253).
There is a report that γ-hydroxybutyric acid (GHB), a GABAB agonist, also improves the fatigue in fibromyalgia patients and is thus effective for fibromyalgia (Pain, 2011, vol. 152, p. 1007-1017). The symptom of fibromyalgia is similar to that of a chronic fatigue syndrome. The GABAB agonist is expected to be effective for the chronic fatigue syndrome.
It has been reported that when GABAB signals are activated, the overexpression of PMP22 genes causing Charcot-Marie-Tooth disease type lA is inhibited (European Journal of Neuroscience, 2004, May, vol. 19(10), p. 2641-2649; and Nature Reviews Drug Discovery, 2012, vol. 11, p. 589).
It has been reported that a GABAB receptor is also present in the peripheral organs, such as spleen, lung, liver, intestine, stomach, esophagus, bladder, and the like (Neuroscience, 2000, vol. 100 (1), p. 155-170; and The Journal of Biological Chemistry, 2000, Oct. 13, vol. 275 (41), p. 32174-32181). Therefore, the GABAB receptor ligand is expected to be applied in the treatment of diseases in the peripheral organs.
Thus, it is believed that a compound activating a GABAB receptor is useful for the prevention or treatment of schizophrenia, CIAS, cognitive impairment, fragile X syndrome, autism spectrum disorder, spasticity, anxiety disorder, substance addiction, pain, fibromyalgia, Charcot-Marie-Tooth disease, or the like.
On the other hand, baclofen has a narrow therapeutic window due to adverse side effects such as sedation, muscle weakness, and the like, and thus, its use is limited. A decrease in motor coordination, a decrease in a body temperature, and the like are also the side effects in baclofen therapy.
A plurality of reports on a positive allosteric modulator (PAM) exist (Molecular Pharmacology, 2001, vol. 60 (5), p. 963-971; Journal of Pharmacology and Experimental Therapeutics, 2004, September, vol. 310 (3), p. 952-963; and Psychopharmacology (Berl), 2011, May, vol. 215(1), p. 117-128). The PAM of the GABAB receptor binds to a receptor at a site different from a site for binding to an endogenous ligand, thereby improving the function of the receptor. The PAM of the GABAB receptor does not exhibit an agonistic activity alone, but increases the affinity to a receptor of an endogenous GABA, and thus, it has an action to increase the Potency and Efficacy of the GABAB receptor. It is believed that due to these properties, the PAM of the GABAB receptor does not exhibit the side effects of the GABAB agonist (for example, the side effects of baclofen as described above) and has useful therapeutic effects.
Therefore, the PAM of the GABAB receptor has little side effects and is expected to be useful for the prevention or treatment of schizophrenia, CIAS, cognitive impairment, fragile X syndrome, autism spectrum disorder, spasticity, anxiety disorder, substance addiction, pain, fibromyalgia, Charcot-Marie-Tooth disease, or the like.
Patent Document 1 discloses a compound of the following general formula, which includes a compound represented by Ex60 as a drug for treating schizophrenia.
[Chem. 1]

(In the formula, definition of R1 includes many groups. As one of those groups, R1 is a cycloalkyl group which may be substituted, or the like. Definition of An includes many groups. As one of those groups, An is an alkyl group which may be substituted, or the like. For the other symbols in the formula, refer to Patent Document 1.)
Patent Document 2 discloses that an mGluR1 inhibitor represented by the following general formula is useful for Parkinson's disease, migraine, or the like.
[Chem. 2]

(In the formula, R2 represents —N(R2a)R2b, —O—R2a, or —S—R2a. For the other symbols in the formula, refer to Patent Document 2.)
Patent Document 3 discloses that a 5-HT antagonist represented by the following general formula is useful as a drug for treating for a neuropathological disease.
[Chem. 3]

(For the symbols in the formula, refer to Patent Document 3.)